Liquid reagent storage and operation of analytical devices

ABSTRACT

Improved mechanisms for storing and introducing liquid volumes in a liquid handling device and, in particular, improved mechanisms for rupturing a liquid storage package to introduce liquid into the device, improvements to the stability of a liquid receiving chamber inside the device and improvements to liquid handling in the receiving chamber are achieved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/584,719,filed May 2, 2017, which in turn is a continuation of application Ser.No. 14/009,433, filed Dec. 9, 2013, now U.S. Pat. No. 9,651,460, issuedMay 16, 2017, which is a National Phase entry of PCT Application No.PCT/M2012/051591, filed Apr. 2, 2012, which claims priority fromPortugal Application No. 105607, filed Apr. 2, 2011, each of which ishereby fully incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a device for storing and handlingliquid and a method for introducing stored liquid into the device, forexample using liquid storage containers such as blister packs. Inparticular, although not exclusively, the present invention relates tocentrifugal microfluidic devices.

BACKGROUND

There are many circumstances where systems for performing analyticalprocedures involve equipment, such as an analyzer, designed to readdisposable cartridges. Known systems and devices performing analyticalprocedures involving liquids contain liquid reagents handled by theanalyzer. In many cases it is preferable to have analyzers withoutliquid handling functions to reduce cost, complexity and maintenance.Consequently, it is desirable to include liquid storage capabilities inthe disposable cartridges.

Several types of analytical systems have been developed in the past,using disk-type cartridges, such as those described in WO2008057000.Different implementations have been developed to store liquids instorage receptacles on cartridges and then open those storagereceptacles when the analysis is to be performed. One of theseimplementations in described in U.S. Pat. No. 5,457,053. Otherimplementations make use of active elements for opening the liquidstorage receptacles, namely by action of optical radiation. One of theseimplementations is described in WO2010084190.

All of these implementations have significant limitations due to theirintrinsic complexity, either in their production processes or in theirrequired level of user interaction.

SUMMARY

Aspects of the invention are defined in the independent claims. Further,optional, features are defined in the dependent claims.

In some embodiments, there is provided a device for handling liquidcomprising a body defining an internal liquid handling structure. Thebody defines a first aperture in an external surface of the body toprovide an inlet port to the liquid handling structure. A bonding layeris secured to the external surface and defines a second aperturepartially overlapping with the first aperture. As a result, the externalsurface is exposed on the first side of the first aperture and thebonding layer partially covers the first aperture on a second side,opposed to the first side. A liquid storage arrangement is secured tothe bonding layer overlapping the first aperture to dispense liquidthrough the first aperture when a pressure exceeding a thresholdpressure is applied to the liquid storage arrangement.

The material properties of the liquid storage arrangement, bonding layerand external surface may be selected such that the liquid storagearrangement reproducibly ruptures in the region of the first side of thefirst aperture in response to pressure exceeding the threshold pressurebeing applied to the liquid storage arrangement.

Advantageously, by disposing the bonding layer between the liquidstorage arrangement and the external surface such that the externalsurface is exposed on one side and covered by the bonding layer on theother side, rupturing of the liquid storage arrangement in areproducible fashion against the external surface where it is exposed isfacilitated. At the same time, the overlap of the bonding layer with thefirst aperture provides a cushion against undesired rupturing in thatregion.

In some embodiments, there is provided a device for handling liquidcomprising a body defining an internal liquid handling structure. Thebody defines a first aperture in an external surface to provide an inletport to the liquid handling structure. A liquid storage arrangement issecured to the external surface to dispense liquid through the firstaperture when a pressure exceeding a threshold pressure is applied tothe liquid storage arrangement. The first aperture defines a sharp edgelevel with the external surface to facilitate rupturing the liquidstorage arrangement.

Advantageously, by providing the first aperture with a sharp edge thatis level with the external surface, manufacturing of the device isfacilitated. For example, the first aperture (and edge) can be definedsimply by an aperture process, for example by stamping. In someembodiments, the sharp edge includes a spike extending into theaperture, the spike being level with the external surface. The presenceof the spike further helps to rupture the liquid storage arrangementreproducibly.

In some embodiments, a device for handling liquid comprises a bodydefining an internal liquid handling structure. The body defines a firstaperture in an external surface to provide an inlet port to the liquidhandling structure. A liquid storage arrangement is secured to theexternal surface to rupture and dispense liquid through the firstaperture when a pressure exceeding a threshold pressure is applied tothe liquid storage arrangement. The liquid handling structure comprisesa liquid receiving chamber for receiving liquid from the liquid storagearrangement through the first aperture, when the liquid storagearrangement is ruptured. To prevent or reduce liquid ingress into aliquid outlet, vent port, or both, of the liquid receiving chamber, dueto rupturing of the liquid storage arrangement, a flow resistingarrangement is disposed within the liquid receiving chamber between thefirst aperture and the liquid outlet, vent port, or both.

Advantageously, the flow resisting arrangement substantially holds theliquid away from the outlet and/or vent port until operation of thedevice begins, in spite of the introduction of liquid into the liquidreceiving chamber from the liquid storage arrangement under highpressure when the liquid storage arrangement ruptures. To this end, theflow resisting arrangement may comprise one or more structural featuresdisposed in the liquid receiving chamber to increase flow resistance tothe liquid and/or provide surface potential energy barriers retainingthe liquid away from the vent port and/or outlet.

In some embodiments, the flow resistance arrangement comprises a supportstructure disposed within the liquid receiving chamber to increase thestructural strength of a wall between the external surface and a liquidreceiving chamber. Other embodiments instead use a support structurewhich does not also have a flow resisting function. The supportstructure may comprise at least one column extending between the walland an exposed surface of the liquid receiving chamber and, in someembodiments, may comprise an array of columns. In one particular form,the array of columns may be arranged as spaced rows of spaced columns ineach row. In this form, each row provides a flow resisting arrangement,increasing resistance to flow by a reduction in flow cross section andalso providing surface tension barriers to a liquid front passing eachrow. Other arrangements may be used to similar effect, for example usingsupport and/or flow resisting structures which comprise one or morewalls traversing the liquid receiving chamber and having orifices toenable liquid passage therethrough.

Further embodiments include the combination of the embodiments describedabove, for example combining the arrangements in relation to the liquidstorage arrangement and its disposition for reproducible rupturing withthe flow resisting and/or structural integrity enhancing features insidethe liquid receiving chamber.

In some embodiments, the liquid storage arrangement may comprise ablister pack. In some particular embodiments, the liquid storagearrangement comprises a foil secured to the external surface and a coversecured to the foil to define a liquid holding chamber between the coverand the foil. In embodiments where a bonding layer is provided betweenthe liquid storage arrangement and the external surface, the foil may besecured to the bonding layer.

In some embodiments, the device is arranged for liquid flow being driventhrough the liquid handling structure by virtue of a centrifugal forceas the device is rotated about an axis of rotation. In some suchcentrifugal embodiments, the liquid handling structure comprises aliquid receiving chamber for receiving liquid from the first apertureand having an outlet port connected to an outlet conduit extending fromthe outlet port. The outlet conduit extends radially inward from theoutlet port to a bend and radially outward from the bend, the bend beingradially outside a fill level of the liquid receiving chamber.

Advantageously, this arrangement ensures that liquid is only dispensedunder rotation from the liquid handling structure if a threshold levelcorresponding to the radial position of the bend is crossed by theliquid, thus ensuring that liquid is only dispensed if a minimum levelis reached. In alternative embodiments, the bend is located radiallyinside of the fill level of the liquid receiving chamber. In suchembodiments, liquid is retained in the liquid handling structure underinitial rotation until the device is slowed down sufficiently for theliquid to be drawn into the outlet conduit by capillary forces to asufficient advance such that the outlet subsequently acts as a siphon toempty the liquid handling structure during rotation (an arrangementtypically referred to as “capillary siphon”).

In some embodiments, the liquid receiving chamber has a radially outwardaspect at the first aperture, which is radially inward of a radiallyoutward aspect of the liquid receiving chamber at an opposed end,opposed to the first aperture. For example, the radially outward aspectmay follow a spiral locus from an end adjacent the first aperture to theopposed end. This arrangement ensures that all liquid in the liquidreceiving chamber is driven towards the opposed end by rotation, thusenabling it to flow through an outlet port disposed at that end todownstream liquid handling structures.

In some embodiments, the first aperture is being arranged to facilitaterupturing of the liquid storage arrangement at a location such thatliquid inside the liquid storage arrangement to be dispensed duringrotation of the device is radially inward of the location. For example,the sharp edge discussed above may be disposed at a radially outwardaspect of the first aperture and/or the overlapping bonding layer regionmay be disposed at a radially inward aspect of the first aperture. Thisarrangement ensures efficient emptying of the liquid storagearrangement. In one particular embodiment, where the first aperture isarranged such that the location is substantially at a radially outermostaspect of the first aperture, substantially all of the liquid in theliquid storage arrangement can be emptied by rotation. For example, tothis end, the sharp edge and/or spike discussed above may be disposed ata radially outermost aspect of the first aperture and/or the overlap ofthe bonding layer may be disposed at a radially innermost aspect of thefirst aperture.

In one embodiment, there is provided a method of introducing liquid intoa device containing a liquid handling structure from a liquid storagearrangement (such as a blister pack) secured to the device overlappingan inlet port for admitting liquid into the device. The method comprisesapplying a pressure to the liquid storage arrangement to rupture theliquid storage arrangement and introduce liquid into the device. Then,the device is rotated to separate gas from the introduced liquid.Subsequently, the device is further rotated to cause liquid to flowthrough the liquid handling structure of the device.

In some embodiments, a method of delivering a volume of liquid to afluid handling device operated by rotation comprises the steps ofproviding the fluid handling device with a communication port inlet andattaching a liquid storage package to the fluid handling device by abonding layer extending outwards from the perimeter of the communicationport inlet, the bonding layer defining a hole through its thickness ofdifferent contour of the communication port inlet, mechanically pressinga liquid storage package to promote rupture of the liquid storagepackage against the edge of the communication port inlet at leastpartially defined within the hole of the bonding layer, and rotating acartridge to extract a liquid content from the liquid storage package tothe fluid handling device to eliminate gas bubbles introduced onrupture.

In some aspects, the fluid handling device contains a receivingstructure adjacent to the communication port to receive the liquid fromthe liquid storage package on rotation and subsequently dispensing theliquid to at least one adjacent structure.

In some aspects, the cartridge contains a receiving structure adjacentto the communication port to receive the liquid from the liquid storagepackage, the receiving structure containing at least one barrierpreventing liquid flow to adjacent structures prior to rotation.

In some aspects, the fluid handling device contains a receivingstructure to receive the liquid from the liquid storage package and isconnected to adjacent structures by a siphon-like outlet conduit, todispense the liquid to adjacent structures by rotation only afterreaching a predefined volume.

In some aspects, the fluid handling device contains a receivingstructure to receive the liquid from the liquid storage package and isconnected to adjacent structures by a siphon-like conduit, to retain theliquid inside the receiving structure at a first rotational frequencyand dispensing the liquid to adjacent structures at a subsequent steprequiring at least one change to the first rotational frequency.

In some aspects, the receiving structure contains a second outlet fromwhich liquid received from the liquid storage package on rotationescapes from the receiving structure, thereby leaving a metered volumein the receiving chamber prior to being dispensed to adjacentstructures.

In some aspects, the predefined level is set to ensure that a minimumvolume of liquid must enter the receiving structure in order to bedispensed to adjacent structures.

In some aspects, the fluid handling device contains a dispensingstructure to receive the liquid from the liquid storage package anddispensing the liquid to adjacent structures, provided with anadditional conduit connected to adjacent structures enabling thecirculation of gas to maintain gas pressure in the system while theliquid is dispensed to adjacent structures.

In some aspects, the fluid handling device contains a receivingstructure to receive the contents from the liquid storage package anddispensing the contents to adjacent structures configured with aspiral-like radially outermost aspect terminated in the outlet conduitfrom which liquid is dispensed.

Further described are analytical rotating cartridges comprising a sealedliquid storage package such as a blister pack attached to a fluidhandling device containing a fluidic communication port designed suchthat the liquid storage package retains its sealing integrity duringhandling but when mechanically pressed ruptures in a predefined positionof the contour the fluidic communication port inlet such that liquidcontent is admitted to the device and upon rotation flows from theliquid storage package into structures defined within the fluid handlingdevice.

Disclosed embodiments relate to the liquid storage components,construction, positioning and operation of the cartridge, in order toenable the rupture of the blister pack when pressed, within a predefinedrange of mechanical force, so that it remains stable when stored andmanipulated while easily ruptured when pressed by an operator or byautomated means. Embodiments also relate to the configurations of thefluid handling device communication port inlet and adjacent fluidicstructures for receiving the liquid from the liquid storage package onrupture in a controlled manner, and removing air bubbles generated onrupture via rotation of the device.

The above summary is not intended to describe each illustratedembodiment or every implementation of the subject matter hereof. Thefigures and the detailed description that follow more particularlyexemplify various embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Subject matter hereof may be more completely understood in considerationof the following detailed description of various embodiments inconnection with the accompanying figures, in which:

FIG. 1A illustrates a fluid handling device in cartridge format andincluding a liquid storage package in blister pack format;

FIG. 1B illustrates further details of FIG. 1A;

FIG. 1C illustrates a cartridge used for operation by rotation andincluding a liquid containing blister pack;

FIG. 2A illustrates a portion of a cartridge having a fluidcommunication port defining a contour adapted for blister pack ruptureand liquid dispensing;

FIG. 2B illustrates a portion of the cartridge of FIG. 2A together witha bonding layer for a liquid containing blister pack;

FIG. 2C illustrates a top view of the cartridge of FIGS. 2A and 2Bhaving a liquid containing blister pack bonded to the bonding layer;

FIG. 3A illustrates a portion of a cartridge having fluidic structuresadapted for blister pack rupture and liquid handling functions foranalytical procedures; and

FIGS. 3B-3D illustrate the operation of the cartridge of FIG. 3A.

While various embodiments are amenable to various modifications andalternative forms, specifics thereof have been shown by way of examplein the drawings and will be described in detail. It should beunderstood, however, that the intention is not to limit the claimedinventions to the particular embodiments described. On the contrary, theintention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the subject matter as defined bythe claims.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates a cartridge including a blister pack according to anembodiment. The cartridge 10 includes a blister pack 20 containing aliquid content 23. The blister pack is made from different materials,typically having an external material 21 that is sufficiently strong tominimize the risk of rupture from its surface both during storage andwhen liquid is released from the blister pack by application ofmechanical pressure, as described below. This material may be analuminum foil, cold form foil, plastic foil, or any type of deformablematerial capable to retain its shape without deteriorating mechanicaland permeation properties.

For most applications demanding a long-time storage, it is preferablefor the material 21 to be moisture-resistant and gas tight. The blisterpack 20 is bonded to the cartridge 10 by a bonding material 24, and thismaterial may be adhesive tape or acrylic glue, or any type of adhesivematerial or material capable of bonding parts by any treatment, namelylight, temperature, pressure or time. A sealing material 22 is disposedbetween the external material 21 and the bonding material 24 and sealsthe blister pack 20. The external material 21 forms a storage chamber 25and a flange 26 surrounding the storage chamber 25. The sealing material22 is sealed to the flange 26 to seal the liquid 23 in the storagechamber 25. The sealing material 22 is sufficiently strong to maintainblister pack integrity but also sufficiently weak to be ruptured whenthe blister pack is pressed in a given range of applied mechanicalforces.

In some embodiments the cartridge 10 is composed typically of threelayers, a lower part 33, a bonding layer 32 and an upper part 31. Theselayers may have different functions, such as for example fluid, andliquid handling, optical or biological functions. However, otherembodiments relate to devices having more or less than three layers,since the methods and mechanisms described will function for otherconstructions from single to multi-layered constructions. The cartridgemay be of different thickness, in some embodiments below 10 mm,preferably below 2 mm.

FIG. 1B provides a detailed view of FIG. 1A. The cartridge is designedand constructed to promote rupture of the blister pack in a region 110.A cut-out region 40 is provided in the cartridge 10 below at least partof the blister pack 20 where the upper part 31 has a cut-out so that theblister pack is free-standing above the cut-out region 40, enablingsealing material 22 to tear or rupture against the contour or outer edgeof the cut-out region 40 in a region 110 under the application of amechanical force to the external material 21. It may be preferable, inmany applications, to have the region 40 at a depth of below 1 mm.

The bonding material 24 defines an aperture through its thickness toallow for fluidic communication between the blister pack 20 andcartridge 10 upon rupture of the sealing material 22. The bondingmaterial 24 extends outwards from the contour of the outer edge ofregion 40 to ensure sealing of the blister pack 20 to the cartridge 10.The outward extent of this bonding area depends of the bonding strengthobtained by the materials and processes employed, and in particular onthe mechanical force needed to rupture the blister pack. In someembodiments, the contour of the aperture of the bonding material 24 isof a different pattern from the outer edge of the free-standing region40. In some embodiments, the bonding material 24 extends inside theperimeter defined by the outer edge of the cut-out region 40 in a region120 and outside the perimeter defined by the outer edge of the cut-outregion 40 to expose an edge at the upper part 31 in a region 110. Thisarrangement favors the rupture of the sealing material 22 in the region110, because a sharp edge of the upper part 31 is exposed in the region110, while the bonding layer cushions this edge in the region 120. Thisarrangement thus can increase the reproducibility of a rupture locationand thus of liquid extraction from the package. Additionally the contourof the aperture of the bonding material 24 can be adjusted, togetherwith the liquid to gas ratio for the blister pack, to tune the range ofmechanical forces required for rupturing the material.

The cartridge described above with reference to FIG. 1A and FIG. 1B canthus be operated without the introduction of additional rupturing partsand therefore be of simple implementation and easy to manufacture. Inparticular, in the case of analytical devices operated by rotation aboutan axis 4, as illustrated in FIG. 1C (omitting the flange 26 of theblister pack 20 for clarity of illustration), it can be advantageous toposition the favored rupture region 110 at an outermost radial aspect ofthe blister pack 20, specifically an outermost radial aspect of thestorage chamber 25, to prevent the entrapment of residual liquidcontained in the storage chamber 25 after rupture and therefore favoremptying of all liquid in the blister pack 20.

The shape of the cut-out region 40, in particular the contour of theouter edge against which material 22 ruptures is an importantconsideration for reproducible blister pack rupture and liquid admissionto the cartridge. This will now be discussed in detail with reference toFIGS. 2A-C.

FIGS. 2A-C illustrate a portion of the cartridge 10 according to anembodiment, having a cut-out region 40 designed to facilitatereproducible blister pack rupture and liquid dispensing. When thecut-out region 40 is too small, the blister pack rupture will only occurwith very high mechanical forces, and therefore not be of practical usein many applications. The same applies when the region 40 is too large,because in this case the blister pack materials 21 and 22 will tend toaccommodate the applied mechanical force by shape change and by elasticdeformation without localized rupture. This latter effect is ofincreasing significance as the depth of the cut-out region 40 decreases.So, in particular for applications having cartridges of less than 2 mmthickness, and a chosen height beneath the cut-out region 40 of lessthan 1 mm, it is advantageous to provide additional features to favorreproducible blister pack 20 rupture onset.

FIGS. 2A and 2B illustrate a part of the cartridge and a blister packaccording to an embodiment. The cartridge 10 is used for operation byrotation about an axis of rotation 4 and contains a cut-out region 40having a non-regular contour shape to facilitate localized rupture ofthe blister pack 20. In particular the cut-out is non-regularly shapedto provide spikes 41 extending inwards, level with an external surfaceat the cartridge 10, specifically upper part 31. The bonding material 24is placed on the external surface to have a portion of the bondingmaterial 24 disposed inside the perimeter defined by the contour of thecut-out region 40 so that the blister pack 20 does not rupture in thatregion as described with reference to region 120 above. The non-regularcontour shape is provided in the region 110 described above, thusfurther facilitating rupture.

FIG. 2C illustrates a top view of the cartridge with the blister pack 20in place on top of the bonding material 24. The size and shape of theblister pack 20 may, in some applications, be optimized to be manuallypressed. The geometry, dimensions, and orientation of the differentelements, cut-out region 40, bonding material 24 and blister pack 20 canbe optimized to retain integrity when stored and manipulated whilstbeing easily ruptured when mechanically pressed by an operator or byautomated means.

Naturally, the above considerations discussed with reference to FIGS.2A-C apply equally to non-rotational embodiments, where liquidpropulsion mechanisms other than a centrifugal force are applied.

FIG. 3A illustrates a part of a cartridge and a liquid blister pack 20according to an embodiment, the cartridge having fluidic structures andcommunication ports arranged to facilitate blister pack rupture, liquiddispensing and analytical performance. For the purpose of illustration,the cartridge is depicted with an outer layer removed to revealunderlying structures and the position of the blister pack 20 on theremoved layer relative to the underlying structures is illustrated by adashed outline.

The cartridge 10 is operated by rotation about an axis 4. The blisterpack 20 is bonded to the cartridge 10 as described above, overlappingthe cut-out region 40 (not visible in FIG. 3A). A liquid receivingstructure 50, optimized for liquid handling functions is provided in theregion of the cut-out region 40 to receive liquid from the blister pack20. (The cartridge 10 may be used in many, different applications, inparticular analytical devices and systems.)

A liquid outlet 53 is connected to an outlet port of the liquidreceiving structure 50 to allow liquid to flow from the liquid receivingstructure 50 to downstream liquid handling structures. Further, a ventconduit 52 is provided to connect the liquid receiving structure 50 toatmospheric pressure or a gas conduit system for equalizing pressurearound the cartridge 10.

The outlet 53 may be configured as a capillary siphon to block liquidflow under rotation as long as capillary action does not draw liquidinto the outlet sufficiently for further rotation to cause liquid to besiphoned from the liquid receiving structure 50. To this end, theradially inner most aspect of the outlet 53, e.g. the crest of thesiphon bend, is disposed radially inwards of the liquid level in thereceiving structure 50 after the liquid 23 has been compacted byrotation. This level is determined by the amount of liquid held by theblister pack 20 and the geometry and dimension of the receivingstructure 50.

Alternatively, the outlet may be arranged as a siphon which primes whena liquid level in the chamber 50 exceeds a level corresponding to theradially innermost point of the outlet 53. This can be achieved bydisposing the radially innermost aspect of the outlet 53 radiallyoutward from the liquid level after the liquid 23 has been compacted.

The liquid receiving structure 50 in some embodiments may be containedin the upper part 31 of the cartridge 10, for example having a thicknessbelow 10 mm, preferably below 1 mm. Equally the liquid receivingstructure or chamber 50 may be defined by one or more of parts 31, 32and 33 individually or in co-operation. The liquid receiving structure50 may contain physical barriers such as posts or pillars 51 for a dualpurpose:

-   -   (i) maintaining the structural integrity of the liquid receiving        structure 50 when the cartridge 10 is manipulated and when the        blister pack 20 is mechanically pressed;    -   (ii) minimize the risk of liquid admitted to the liquid        receiving structure 50 on rupture to flow into adjacent        structures before this is desirable, e.g. prior to rotation.

The second purpose can be of paramount importance for many applicationsin which the cartridge 10 contains a plurality of fluidic structuresoperated by rotation, and where capillary effects play a significantrole. In particular, when blister pack 20 is pressed and ruptured, thenat least part of the liquid content 23 will move into the receivingstructure 50. Due to the mechanical force applied and gas contained inthe blister pack, the liquid content 23 admitted to the receivingstructure 50 may contain gas bubbles which may compromise subsequentcartridge operation. Additionally, if part of liquid 23 admitted to thereceiving structure 50 reaches the outlet 53 prior to rotation then theliquid may also flow by capillary action prior to an initial phase ofrotation, compromising the liquid functions for which the cartridge wasdesigned.

Further, many applications and devices require the use of closedcircuits, for both liquid and gas flow. This fact is relevant forapplications of blood analysis or other processing or analyticalapplications where contamination from or to the sample may beundesirable. In such circumstances, gas displacement during liquid flowcan be critical for proper operation of the device to avoid gas pressurevariations which will also affect the flow of the liquid. For example,in some embodiments the liquid receiving structure 50 is provided withthe vent conduit 52 connecting to adjacent structures where liquid 23will flow, to avoid gas pressure variations in the device while it isbeing operated. This would be compromised if the vent conduit 52 wouldbe blocked by a liquid plug.

Therefore, barriers to liquid flow such as pillars 51 are provided inthe liquid receiving structure to prevent liquid advancing from theblister pack into the outlet 53 prior to initial rotation and to preventliquid ingress into the vent conduit 52 by limiting uncontrolled liquidflow prior to rotation. In one specific embodiment, as illustrated inFIGS. 3A-3D, an array of pillars 51 in the form of several spaced rowsis provided in the liquid receiving structure 50.

Operation of the device is now described with reference to FIGS. 3B-3D.

FIG. 3B illustrates a state after rupturing the blister pack and priorto rotation. The blister pack 20 has been mechanically pressed and hasruptured. Liquid 23 fills part of the receiving structure 50, along withgas 61 released from the blister pack on rupture. The pillars 51 preventliquid from reaching the outlet 53 and vent conduit 52.

FIG. 3C illustrates a state during an initial phase of rotation. Theliquid 23 is driven towards the outermost radial aspects of thereceiving structure 50 by the action of the centrifugal force, and as aresult gas 61 moves inwards leaving a compact of the liquid 23 in thereceiving structure 50. Liquid retained in the blister pack afterrupture will also flow into receiving structure 50 by the action of thecentrifugal force provided that the fluidic communication induced onrupture is radially beyond the liquid position inside the blister pack.In some embodiments, liquid dispensing to adjacent structures anddownstream circuits is delayed for a sufficient amount of time so thatthe gas 61 is removed from the liquid content 23, by forming the liquidcompact 62 against the outermost radial aspects of the receivingstructure 50. In some embodiments, this may be achieved as describedabove by designing the outlet 53 with a portion of its length radiallyinwards from the outlet port of the receiving structure 50, followed byanother portion extending radially outwards from the innermost radialposition of the outlet. In some embodiments, the outlet 53 is designedsuch that a minimum amount of liquid 23 must be admitted to thereceiving chamber 50 or otherwise liquid will not be dispensed tofurther structures. These embodiments are useful, for example, tocontrol the liquid content of the blister, or efficiency of the rupturemechanism and to eventually discard devices in which a minimum amount ofliquid required for adequate operation of the device has not beenreceived from the blister pack 20.

As described above, the outlet 53 has, in some embodiments, asiphon-like shape, in order to retain the liquid 23 in the receivingstructure 50 until a pre-defined liquid volume has been admitted to thechamber. Alternatively, in some embodiments this channel may be arrangedas a capillary siphon in which all liquid admitted from the blister pack20 is retained in the receiving chamber 50 at a first rotationalfrequency for any desired period of time. After this period, liquid maybe dispensed to adjacent structures after at least one change inrotational frequency, to enable the liquid to advance into the outlet 53by capillary action and then dispensing the liquid at this or anotherrotational frequency. In other embodiments, also using the capillarysiphon outlet arrangement described above, the receiving structure 50contains a second outlet from which liquid in excess of a predefinedvolume escapes from structure 50 during a first rotation, to thendispense a metered liquid volume at subsequent steps. The use of welldefined, or metered, liquid volumes can be of critical importance tomany analytical procedures as, for example, dilution ratios andconcentrations are dependent on liquid volumes.

FIG. 3D illustrates a state during further rotation and liquiddispensing. When the liquid 23 reaches a certain level defined by theinnermost radial position of the outlet conduit 53, the liquid 23 willstart to flow to adjacent downstream structures (alternatively, thestart of liquid flow through the outlet 53 can be controlled by therotational frequency, as described above). The receiving structure 50is, in some embodiments, shaped to minimize the amount of liquid thatremains entrapped in its volume. In particular, the outermost radialaspect of the receiving structure 50, along its angular extent,increases in radial extent towards the outlet port where outlet 53starts, such as for example having an outermost perimeter following aspiral locus.

As described above, the vent conduit 52 ensures a gas pressureequilibrium within the cartridge 10 and therefore prevents liquid flowbeing affected by gas pressure variations. The vent port of the liquidreceiving structure 50 where vent conduit 52 starts, is disposed in aradially inward aspect of the liquid receiving chamber 50 to reduce therisk of blocking the vent conduit 52 by the presence of liquid uponrupture and subsequent rotation of the device.

It can be noted that, by placing the vent conduit 52 radially inward ofthe outlet port, the risk of clogging is reduced by liquid being drivenradially outward during rotation. This can help to maintain pressureequilibration.

After liquid dispensing from the blister pack into adjacent downstreamstructures has occurred via the liquid receiving structure 50 the liquidreceiving structure 50 is again in an empty state as illustrated in FIG.3A. The device 10 may then be operated according to subsequent,application specific, liquid handling functions.

In some embodiments the receiving structure 50 may also provideadditional functions, such as aliquoting functions. For this purpose, acartridge 10 may have a liquid receiving structure 50 with a multitudeof outlets 53, placed in such a way that multiple liquid volumes aredispensed from the liquid blister pack 20 into different downstreamstructures. Additionally, solid reagents may be incorporated in thereceiving structure 50 which are re-suspended the moment liquid isadmitted to the structure until no liquid remains. Embodiments may havemore than one liquid storage package incorporating different liquidreagents and bonded to a single cartridge. These may be rupturedsimultaneously or at different stages of the analytical procedure (orrotation protocol), or even allow for rupturing of only those packageswhich are required for a particular procedure, thus enabling the use ofidentical cartridges for applications requiring different reagents.

The above description of embodiments is made by way of illustration andnot for the purpose of limitation. In particular, the above description,being made in terms of a “blister pack”, is not so limited and equallyapplies to any other suitable liquid storage arrangement from whichliquid can be released by mechanical pressure. Many alterations,modifications and juxtapositions of the features described above willoccur to the person skilled in the art and form part of the invention.

Various embodiments of systems, devices, and methods have been describedherein. These embodiments are given only by way of example and are notintended to limit the scope of the claimed inventions. It should beappreciated, moreover, that the various features of the embodiments thathave been described may be combined in various ways to produce numerousadditional embodiments. Moreover, while various materials, dimensions,shapes, configurations and locations, etc. have been described for usewith disclosed embodiments, others besides those disclosed may beutilized without exceeding the scope of the claimed inventions.

Persons of ordinary skill in the relevant arts will recognize that thesubject matter hereof may comprise fewer features than illustrated inany individual embodiment described above. The embodiments describedherein are not meant to be an exhaustive presentation of the ways inwhich the various features of the subject matter hereof may be combined.Accordingly, the embodiments are not mutually exclusive combinations offeatures; rather, the various embodiments can comprise a combination ofdifferent individual features selected from different individualembodiments, as understood by persons of ordinary skill in the art.Moreover, elements described with respect to one embodiment can beimplemented in other embodiments even when not described in suchembodiments unless otherwise noted.

Although a dependent claim may refer in the claims to a specificcombination with one or more other claims, other embodiments can alsoinclude a combination of the dependent claim with the subject matter ofeach other dependent claim or a combination of one or more features withother dependent or independent claims. Such combinations are proposedherein unless it is stated that a specific combination is not intended.

Any incorporation by reference of documents above is limited such thatno subject matter is incorporated that is contrary to the explicitdisclosure herein. Any incorporation by reference of documents above isfurther limited such that no claims included in the documents areincorporated by reference herein. Any incorporation by reference ofdocuments above is yet further limited such that any definitionsprovided in the documents are not incorporated by reference hereinunless expressly included herein.

For purposes of interpreting the claims, it is expressly intended thatthe provisions of 35 U.S.C. §112(f) are not to be invoked unless thespecific terms “means for” or “step for” are recited in a claim.

Various embodiments of systems, devices, and methods have been describedherein. These embodiments are given only by way of example and are notintended to limit the scope of the claimed inventions. It should beappreciated, moreover, that the various features of the embodiments thathave been described may be combined in various ways to produce numerousadditional embodiments. Moreover, while various materials, dimensions,shapes, configurations and locations, etc. have been described for usewith disclosed embodiments, others besides those disclosed may beutilized without exceeding the scope of the claimed inventions.

Persons of ordinary skill in the relevant arts will recognize that thesubject matter hereof may comprise fewer features than illustrated inany individual embodiment described above. The embodiments describedherein are not meant to be an exhaustive presentation of the ways inwhich the various features of the subject matter hereof may be combined.Accordingly, the embodiments are not mutually exclusive combinations offeatures; rather, the various embodiments can comprise a combination ofdifferent individual features selected from different individualembodiments, as understood by persons of ordinary skill in the art.Moreover, elements described with respect to one embodiment can beimplemented in other embodiments even when not described in suchembodiments unless otherwise noted.

Although a dependent claim may refer in the claims to a specificcombination with one or more other claims, other embodiments can alsoinclude a combination of the dependent claim with the subject matter ofeach other dependent claim or a combination of one or more features withother dependent or independent claims. Such combinations are proposedherein unless it is stated that a specific combination is not intended.

Any incorporation by reference of documents above is limited such thatno subject matter is incorporated that is contrary to the explicitdisclosure herein. Any incorporation by reference of documents above isfurther limited such that no claims included in the documents areincorporated by reference herein. Any incorporation by reference ofdocuments above is yet further limited such that any definitionsprovided in the documents are not incorporated by reference hereinunless expressly included herein.

For purposes of interpreting the claims, it is expressly intended thatthe provisions of 35 U.S.C. §112(f) are not to be invoked unless thespecific terms “means for” or “step for” are recited in a claim.

1-17. (canceled)
 18. A method of introducing liquid into a fluidhandling device comprising a liquid handling structure from a liquidstorage arrangement secured to the fluid handling device overlapping aninlet port for admitting liquid into the fluid handling device, themethod comprising: applying a pressure to the liquid storage arrangementto rupture the liquid storage arrangement and introduce liquid into thefluid handling device; rotating the fluid handling device to separategas from the introduced liquid; and subsequently rotating the fluidhandling device to cause liquid to flow through the liquid handlingstructures of the fluid handling device.
 19. The method of claim 18,wherein the fluid handling device further comprising a communicationport inlet and a liquid storage package attached to the fluid handlingdevice by a bonding layer extending outwards from the perimeter of thecommunication port inlet, the bonding layer defining a hole through itsthickness of different contour of the communication port inlet, andwherein rotating the fluid handling device to separate gas from theintroduced liquid comprises mechanically pressing a liquid storagepackage to promote rupture of the liquid storage package against theedge of the communication port inlet at least partially defined withinthe hole of the bonding layer, and rotating a cartridge to extract aliquid content from the liquid storage package to the fluid handlingdevice to eliminate gas bubbles introduced on rupture.
 20. The method ofclaim 19, wherein the cartridge contains a receiving structure adjacentto the communication port to receive the liquid from the liquid storagepackage, the receiving structure containing at least one barrierproviding a resistance to liquid flow to adjacent structures prior torotation.
 21. The method of claim 18, wherein the fluid handling devicecontains a receiving structure to receive the liquid from the liquidstorage package and is connected to adjacent structures by a siphon-likeoutlet conduit, to dispense the liquid to adjacent structures byrotation only after reaching a predefined volume.
 22. The method ofclaim 18, wherein the fluid handling device contains a receivingstructure adjacent to the inlet port to receive the liquid from theliquid storage package on rotation and subsequently dispensing theliquid to at least one adjacent structure.
 23. The method of claim 18,wherein the fluid handling device contains a receiving structure toreceive the liquid from the liquid storage package and is connected toadjacent structures by a siphon-like conduit, to retain the liquidinside the receiving structure at a first rotational frequency anddispensing the liquid to adjacent structures at a subsequent steprequiring at least one change to the first rotational frequency.
 24. Themethod of claim 23, wherein the receiving structure contains a secondoutlet from which liquid received from the liquid storage package onrotation escapes from the receiving structure, thereby leaving a meteredvolume in the receiving chamber prior to being dispensed to adjacentstructures.
 25. The method of claim 18, wherein a predefined level isset to ensure that a minimum volume of liquid must enter the receivingstructure in order to be dispensed to adjacent structures.
 26. Themethod of claim 18, wherein the fluid handling device contains adispensing structure to receive the liquid from the liquid storagepackage and dispensing the liquid to adjacent structures, provided withan additional conduit connected to adjacent structures enabling thecirculation of gas to maintain gas pressure in the system while theliquid is dispensed to adjacent structures.
 27. The method of claim 18,wherein the fluid handling device contains a receiving structure toreceive the contents from the liquid storage package and dispensing thecontents to adjacent structures configured with a spiral-like radiallyoutermost aspect terminated in the outlet conduit from which liquid isdispensed.
 28. The method of claim 18, wherein the fluid handling devicecomprises a cartridge containing a receiving structure adjacent to thecommunication port to receive the liquid from the liquid storagepackage, the receiving structure containing at least one barrierproviding a resistance to liquid flow to adjacent structures prior torotation.
 29. The method of claim 18, wherein the fluid handling devicecontains a receiving structure to receive the liquid from the liquidstorage package and dispensing the liquid to adjacent structures,provided with an additional conduit connected to adjacent structuresenabling the circulation of gas to maintain gas pressure in the systemwhile the liquid is dispensed to adjacent structures.
 30. The method ofclaim 18, wherein the fluid handling device contains a dispensingstructure to dispense the contents from the liquid storage package anddispensing the contents to adjacent structures configured with aspiral-like radially outermost aspect terminated in the outlet conduitfrom which liquid is dispensed.
 31. The method of claim 18, wherein thefluid handling device contains a receiving structure to receive theliquid from the liquid storage package, and wherein once the liquid fromthe liquid storage package is received in the receiving structure, theliquid is capable of being dispensed to adjacent structures, providedwith an additional conduit connected to adjacent structures enabling thecirculation of gas to maintain gas pressure in the system while theliquid is dispensed to adjacent structures.
 32. The method of claim 31,wherein the fluid handling device contains a receiving structure toreceive the liquid from the liquid storage package, and wherein thereceiving structure is capable of dispensing the liquid received fromthe liquid storage package to adjacent structures configured with aspiral-like radially outermost aspect terminated in the outlet conduitfrom which liquid is dispensed.